the charity dedicated to defeating pancreatic cancer by funding innovative research

3 April 2012

Researchers have discovered that the cholesterol lowering drug, TO901317, increases the effectiveness of chemotherapy on pancreatic cancer.

TO901317 reduces the amount of cholesterol in a cell by ‘switching on’ receptors known as liver x receptors, which results in the redistribution of cholesterol throughout the body. Liver x receptors also block a cell signalling pathway called the Hedgehog pathway. Over-activity of the Hedgehog pathway is a known trigger of many types of cancer including pancreatic.

The team treated mice with pancreatic tumours with TO901317 and the chemotherapy drug, gemcitabine. When given alone, T0901317 did not affect tumour growth, but when used in combination with gemcitabine, the activity of the Hedgehog pathway was significantly reduced and the tumours shrank. .

Professor William Matsui of the John Hopkins University explained that chemotherapy drugs can have difficulty finding cancerous cells, because pancreatic tumours are crowded with thick scar tissue. By blocking the Hedgehog pathway, this may help pancreatic cancer drugs penetrate the tumour more effectively to attack cancer cells.

He told the meeting that new drugs designed to target the Hedgehog pathway are currently under development but all of these target the same protein in the Hedgehog pathway – but tumours are known to mutate this protein, which makes cancer cells resistant to these new therapies. “Activating liver x receptor could be an alternative target for blocking the Hedgehog pathway,” says Prof Matsui.

The team, in association with Professor Michael Jung and Dr Frank Stappenbeck at the Chemistry department of UCLA, are currently developing novel, more effective and safer liver X receptor activators for use in targeting pancreatic cancer.

Investigating the Hedgehog signalling pathway is also the subject of a PCRF-funded project, which you can read about here.